Effects of early life seizures on coordination of hippocampal–prefrontal networks: Influence of sex and dynamic brain states

Abstract

Objective: Early life seizures (ELSs) alter activity-dependent maturation of neuronal circuits underlying learning and memory. The pathophysiological mechanisms underpinning seizure-induced cognitive impairment are not fully understood, and critical variables such as sex and dynamic brain states with regard to cognitive outcomes have not been explored. We hypothesized that in comparison to control (CTL) rats, ELS rats would exhibit deficits in spatial cognition correlating with impaired dynamic neural signal coordination between the hippocampus and medial prefrontal cortex (mPFC). Methods: Male and female rat pups were given 50 flurothyl-induced seizures over 10 days starting at postnatal Day 15. As adults, spatial cognition was tested through active avoidance on a rotating arena. Microwire tetrodes were implanted in the mPFC and CA1 subfield. Single cells and local field potentials were recorded and analyzed in each region during active avoidance and sleep. Results: ELS males exhibited avoidance impairments, whereas female rats were unaffected. During avoidance, hippocampus-mPFC coherence was higher in CTL females than CTL males across bandwidths. In comparison to CTL males, ELS male learners exhibit increased coherence within theta bandwidth as well as altered bursttiming in mPFC cell activity. Hippocampus-mPFC coherence levels are predictive of cognitive outcome in the active avoidance spatial task. Significance: Spatial cognitive outcome post-ELS is sex-dependent, as females fare better than males. ELS males that learn the task exhibit increased mPFC coherence levels at low-theta frequency, which may compensate for ELS effects on mPFC cell timing. These results suggest that coherence may serve as a biomarker for spatial cognitive outcome post-ELS and emphasize the significance of analyzing sex and dynamic cognition as variables in understanding seizure effects on the developing brain.

Dynamic θ Frequency Coordination within and between the Prefrontal Cortex-Hippocampus Circuit during Learning of a Spatial Avoidance Task

“…To quantify the effects of behavior and cognitive demand on signal coordination, we examined “avoidance arcs” during performance of the active avoidance task as in prior studies ( Barry et al, 2020 ; Niedecker et al, 2021 ). During task performance, rats must remember to transition from a resting state, at least once every minute, avoid being rotated into the shock zone by running counter the direction of arena rotation.…”

“…θ-Scale coordination within and between the medial prefrontal cortex (mPFC) and hippocampus (HC) has been implicated in spatial cognitive outcomes in neurodevelopmental disease models such as schizophrenia ( Lee et al, 2012 ), early-life seizures ( Kleen et al, 2011 ; Holmes et al, 2015 ; Niedecker et al, 2021 ), and cortical dysplasia ( Hernan et al, 2020 ). The mPFC has long been directly connected to working memory, behavioral flexibility, and planning; all of which are critical faculties for goal-oriented behavior ( Vinken et al, 1969 ; Fuster, 1989 ; Passingham, 1993 ; Spiers, 2008 ; O’Neill et al, 2013 ; Spellman et al, 2015 ; Tamura et al, 2017 ).…”

“…In this vein, cell activity in the mPFC has also been proposed to have an important role in avoidance learning in aversive contexts ( Adhikari et al, 2010 ; Padilla-Coreano et al, 2016 , 2019 ) and the extinction-learning of aversive fear conditioning stimuli ( Santini et al, 2004 ; Quirk et al, 2006 ; Peters et al, 2009 ; Rosas-Vidal et al, 2014 , 2018 ; Martínez-Rivera et al, 2019 ). The HC θ phase coordination of mPFC cell activity has also been closely linked to learning and spatial processing ( Hyman et al, 2005 ; Jones and Wilson, 2005 ; Siapas et al, 2005 ; Negrón-Oyarzo et al, 2018 ; Zielinski et al, 2019 ; Niedecker et al, 2021 ) and may direct attention to task-relevant representations required to solve spatial or working memory tasks ( Hyman et al, 2010 , 2011 ; O’Neill et al, 2013 ; Ito et al, 2015 ).…”

“…Although slow frequency oscillations such as θ provide long-range windows of temporal organization ( Siapas et al, 2005 ; Lee et al, 2012 ; 80–20 ms per cycle), it is not known whether there are meaningful differences in the degree of θ coordination between the mPFC and its monosynaptic connections to the ventral hippocampus (vHC; Jay and Witter, 1991 ; Jay et al, 1996 ; Hoover and Vertes, 2007 ; Liu and Carter, 2018 ; Anastasiades and Carter, 2021 ) and its indirect, polysynaptic connections to the dorsal hippocampus (dHC) via bidirectional cortical intermediaries and thalamic nuclei ( Thierry et al, 2000 ; Ito et al, 2015 ; Eichenbaum, 2017 ; Dolleman-van der Weel et al, 2019 ; Anastasiades and Carter, 2021 ). Moreover, while levels of mPFC-HC phase coordination can correlate with or be predictive of spatial cognitive outcomes ( Lee et al, 2012 ; Niedecker et al, 2021 ), and 8-Hz coordination has been shown to be necessary for learned avoidance ( Padilla-Coreano et al, 2019 ), it is not known whether shifts to specific θ frequencies reflect changes in cognitive demand and circuit throughput during spatial avoidance in a similar manner as cortical processing of sensory stimuli ( Tort et al, 2010 ; Schulz et al, 2015 ).…”

“…In contrast, cholinergic dependent and alert immobility related type 2 θ, is typically <7 Hz and linked to arousal, anxiety or novelty at slow speeds or at rest ( Vanderwolf, 1969 ; Kramis et al, 1975 ; O’Keefe and Nadel, 1978 ; Sainsbury et al, 1987 ; Kelemen et al, 2005 ; Jeewajee et al, 2008 ; Buzsáki and Moser, 2013 ). Yet beyond this distinction in hippocampal θ frequency, it remains unknown whether mPFC-HC θ subfrequencies have functional significance for spatial cognition ( Niedecker et al, 2021 ) or vigilance ( Kramis et al, 1975 ; Wells et al, 2013 ) during active avoidance.…”